CNS & neurological disorders drug targets最新文献

Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by β-amyloid (Aβ) plaque accumulation and cognitive decline. Early intervention targeting Aβ production may mitigate AD progression. This study investigated the neuroprotective effects of hesperetin, a citrus flavonoid, in APPswe/PS1dE9 transgenic mice.

Methods: APPswe/PS1dE9 mice (3 months old) were administered hesperetin (20, 40, and 80 mg/ kg/day) for 6 months. Cognitive function was assessed using the Morris water maze and the Barnes maze. Neuronal morphology in the hippocampal CA1 region was examined using thionin staining. Aβ40, Aβ42, β-secretase, and γ-secretase levels in brain tissue and serum were measured by ELISA, and tau protein expression was analyzed by Western blotting.

Results: Hesperetin-treated mice exhibited improved learning and memory, reduced neuronal degeneration, and lower tau expression. Brain tissue showed decreased Aβ40, Aβ42, and secretase levels, whereas serum Aβ levels increased, suggesting enhanced Aβ clearance.

Discussion: Hesperetin may attenuate AD pathology by inhibiting β- and γ-secretase activity, reducing Aβ production, and promoting Aβ efflux to peripheral circulation.

Conclusion: Early hesperetin intervention demonstrates potential as a therapeutic strategy for AD by modulating Aβ metabolism and preserving cognitive function.

Alzheimer's Disease (AD) is a neuronal illness that disrupts behavior, cognitive, and functional abilities. The development of AD is progressive, continuous, and irreversible, from preclinical illness to mild cognitive or even behavioral disturbance to dementia (a medical brain condition) triggered by AD. Worldwide accepted hypotheses of AD are called the amyloid-cascade and hyperphosphorylated tau-cascade hypotheses, and enzymes are implicated in the pathophysiology of AD directly or indirectly. There is an implication of enzymes in the pathophysiology of AD. Enzymes include proteases (e.g., neprilysin), kinases (e.g., glycogen synthase kinase-3), cholinergic enzymes (e.g., acetylcholinesterase), metalloproteinases (e.g., matrix metalloproteinases), and oxidative stress-related enzymes (e.g., superoxide dismutase). However, during abnormal or early Alzheimer's Disease (AD) conditions, the activity and expression of these enzymes are altered in biological samples such as blood, urine, and cerebrospinal fluid (CSF) in patients with early AD when examined. These alterations in enzyme activity in early AD demonstrate the potential of these enzymes as biomarkers. Early detection of AD in its early stages is crucial for effective control and treatment of the disease. Existing diagnostic techniques rely mainly on neuroimaging and medical evaluation. Through this technique, we can only diagnose the advanced or late stage of AD. Therefore, there is a crucial need to establish valid biomarkers that might assist in the early detection of AD. Enzymatic targets have come to light as a promising alternative for the development of selective and sensitive diagnostic assays. This review aims to investigate the potential of enzymes as an enzymatic target for early AD diagnosis, emphasizing their diagnostic use and fundamental mechanisms. Here, we summarize the role or implication of 25 enzymes in the pathophysiology of AD in the early stage.

Introduction: Anxiety disorders, characterized by overwhelming fear, affect more than 30% of the global population. Recent evidence indicates that antihypertensive medications could offer symptomatic relief for anxiety, supporting their potential for repurposing. The objective is to investigate the anxiolytic-like effects of an enalapril formulation.

Methods: 60 Swiss mice (30 ± 5 g, aged 6-8 weeks) were randomly assigned to groups and received oral treatments with either vehicle (10 mL/kg), diazepam (DZP, 5 mg/kg), reference enalapril (ENAR), enalapril formulation (ENAF), losartan (LOS), or propranolol (PRO), each at a dose of 10 mg/kg. After 60 minutes, the animals were exposed to 5 minutes of exploratory activity in the open field, elevated plus maze (EPM), light-dark box (LDB), and a minute of rotarod.

Results: One-way ANOVA demonstrated differences for the total crossing (p=0.0001), freezing time (p=0.0001), number of rearing (p=0.002), time spent (p=0.002), and crossing at the center (p=0.0001) of the open field. Unlike in the rotarod (p>0.05), the ENAR, ENAF, LOS, and PRO elicit increases (p<0.05) in the total number of arm entries and time spent on the open arms of EPM while increasing the number of transitions (p<0.05) and time spent in the light area of the LDB (p=0.001). In silico screening suggests stability of interaction with several amino acid residues overlapping with the flumazenil binding site, with the binding energy (ΔE) = -22.59kcal/mol towards the benzodiazepine binding site (flumazenil ΔE = -43.92kcal/mol).

Discussion: The repositioning of drugs available to the population is an interesting approach toward the discovery of alternative or add-on treatments for anxiety. Ongoing resort to repurposing, reusing, reprofiling, and rediscovery of "old" drugs for a new indication seems to be an interesting way out of failures, the expensive and slow pace of new drug discovery.

Conclusion: Enalapril demonstrates anxiolytic-like properties, further insights into the GABAergicrenin- angiotensin-aldosterone mechanistic hypothesis.

Tobacco consumption is a worldwide issue that has significant health repercussions. Each year, related diseases result in an expenditure of billions of dollars in healthcare costs and diminished productivity. People are becoming more conscious of the fact that quitting smoking at any age can prolong life and lessen many of the negative consequences of smoking. While there are currently some treatment options available, there is still a substantial demand for novel and efficient pharmacotherapies to assist smokers in achieving and sustaining long-term sobriety. The symptoms of nicotine withdrawal are a significant obstacle to cessation and must be alleviated to prevent early recurrence. This article has discussed the neurotransmitters that are responsible for nicotine reward and the anatomical structures implicated in nicotine withdrawal. A simple hypothesis regarding tobacco addiction posits that nicotine is the primary addictive constituent of tobacco. Anxiety, depression, and stress have intricate effects on every facet of nicotine dependency, including the withdrawal experience. Smokers commonly utilize smoking as a means to reduce tension and anxiety, as it is believed to have a relaxing effect. This increasing knowledge offers a detailed understanding of the mechanisms behind existing and future smoking cessation treatments. Therefore, nicotine withdrawal is a significant factor influencing continued nicotine product use and contributes to unsuccessful cessation attempts. In conclusion, nicotine withdrawal may lead to cognitive changes and attention disturbances in the short term and enhance exercise-related physical abilities in the long term.

Glioblastoma multiforme (GBM), a fatal malignant brain tumor, represents a challenge in terms of developing new treatments. Solutions have been proposed in connection with anti-tumor immune responses, generally T cell strategies, including techniques targeting growth factors, particularly IGF-I, the primary cancer growth factor, and its signal transduction pathways. The objective of this review is to assess the immunogene mechanism targeting IGF-I, which constitutes the basis of the described cancer gene therapy for GBM, stemming from brain neoplastic development studies. The GBM gene therapy, based on new strategies of anti-gene IGF-I techniques, including antisense or triple helix, has been combined with phytochemicals (phenolics) and nanotechnologies (theranostic nanoparticles). The three approaches have modulated IGF-I expression together, inducing common signal transduction pathways: IGF-I-R, TK/PI3K/AKT/TLR/MAPK & JAK/STAT. These signals have transformed in vitro neoplastic glioma cells into immunogenic cells. These immunogenic cells, which express MHC-1 and B7, produce a strong T CD8 anti-tumour immune response after in vivo injection. The combined strategy of anti-IGF-I/phytochemical/nanotechnology vaccines has shown promising clinical results, with patient survival of up to two and three years in some cases. The obtained results are discussed in parallel with other immunotherapies and antitumour vaccine studies that involve the immunogenicity mechanism.

Ischemic stroke (IS) globally threatens human health due to its limited treatment options and the severity of its complications, which often result in long-term disability. SIRT1, a key member of the sirtuin family, plays a pivotal role in regulating various cellular processes by facilitating the deacetylation of both histone and non-histone substrates. As a critical regulator, SIRT1 is involved in multiple pathophysiological processes, including neuroinflammation, regulated cell death (RCD), oxidative stress, and more, which are central to the progression of IS. In IS, SIRT1 exerts its effects through a variety of specific mechanisms, including promoting NF-κB and FoxO deacetylation, enhancing eNOS expression, inhibiting NOX production, and suppressing the TLR and NLRP3 inflammasome pathways, which contribute to the regulation of RCD. These actions influence various forms of cell death, such as apoptosis, ferroptosis, pyroptosis, autophagic-dependent cell death, necroptosis, and cuproptosis. Additionally, SIRT1 may function upstream of the RIPK1/RIPK3/ MLKL pathway, thereby contributing to necroptosis activation. Moreover, SIRT1 modulators, including resveratrol, SRT1720, EX-527, and Sirtinol, have demonstrated neuroprotective effects in preclinical and clinical trials. However, challenges such as blood-brain barrier (BBB) permeability, drug stability, and target specificity need to be addressed. Thus, future research should aim to overcome these obstacles and develop novel SIRT1 modulators with better clinical translation potential, ultimately improving IS treatment outcomes. This review further explores the therapeutic implications of SIRT1 modulation in IS treatment and highlights the urgent need for more clinical validation to support its broader application.

Introduction: Traumatic brain injury (TBI) is a significant cause of mortality and longterm disability worldwide, presenting a critical challenge to clinical management and public health. It triggers a cascade of complex biochemical events, such as oxidative stress and inflammation, that worsen neurological and cognitive deficits over time. This review aims to synthesize current evidence on how nutritional interventions, particularly vitamins, omega-3 fatty acids, and probiotics, may mitigate these pathological processes and support brain recovery.

Method: Literature was systematically searched using PubMed, Google Scholar, the National Institutes of Health, and The Nutrition Source. Studies included preclinical and clinical research on TBI interventions involving vitamins, omega-3 fatty acids, and probiotics. The PRISMA 2020 guidelines were followed, and the study selection process is illustrated in Fig. (1), which outlines the identification, screening, eligibility, and inclusion phases.

Results: These nutritional supplements demonstrate anti-inflammatory, antioxidant, and neuroprotective effects, supporting synaptic plasticity, gut-brain axis integrity, and neuronal repair.

Discussion: This review systematically evaluates the role of vitamins, omega-3 fatty acids, and probiotics in the management of TBI, focusing on both clinical and preclinical findings to assess their therapeutic potential, particularly in relation to secondary injury mechanisms for which current treatments are limited.

Conclusion: Robust preclinical data support the neurotherapeutic potential of these supplements; however, clinical validation is still in development. Future studies should prioritize standardized dosing, optimal timing of administration, and strain-specific probiotic evaluation to ensure the effective integration of probiotics into TBI management.

Introduction: Insomnia is a recognised risk factor for type 2 diabetes (T2DM). Although benzodiazepines (BDZs) are commonly prescribed for the treatment of insomnia, evidence regarding their use and the onset of T2DM among individuals with insomnia remains limited. This study aimed to assess the association between BDZ use and incident T2DM in a population with insomnia.

Methods: Within the UK Biobank prospective cohort of participants reporting insomnia, we examined the association between BDZ use and the risk of incident T2DM using multivariable adjusted Cox regression models. Robustness was evaluated through propensity score matching, inverse probability of treatment weighting, and competing risk analyses. Drug target Mendelian randomisation was conducted to explore potential causal relationships between BDZ pharmacological targets and T2DM.

Results: Among 125,789 participants with insomnia, 119 of 1,524 BDZ users (7.8 per cent) and 6,833 of 124,265 non-users (5.5 per cent) developed incident T2DM over a median follow-up of 14.3 years. The primary multivariable Cox regression and all sensitivity analyses showed no association between BDZ use and T2DM risk. Drug target Mendelian randomisation further demonstrated no significant causal effect of BDZ target gene expression on T2DM development.

Discussion: These findings indicate that BDZ use does not materially influence T2DM risk in individuals with insomnia, despite theoretical concerns regarding metabolic effects. The consistency across observational and genetic approaches supports the robustness of this null association and may ease concerns about long-term metabolic safety in clinical settings.

Conclusion: Evidence from both cohort analyses and drug target Mendelian randomisation suggests that BDZ use does not significantly increase the risk of T2DM among UK Biobank participants with insomnia.

Introduction: Sodium-glucose transport protein 2 (SGLT-2) inhibition regulates neuronal excitability by shifting glucose metabolism toward ketone utilization and by reducing oxidative stress and inflammation. Based on these mechanisms, this study investigated the anticonvulsant and anti-inflammatory effects of empagliflozin, a SGLT-2 inhibitor with neuroprotective properties, in a penicillin-induced epilepsy model.

Methods: Thirty-five adult male Wistar rats were randomly divided into five groups (n = 7/group): sham, control (penicillin only), empagliflozin (10 mg/kg), diazepam (5 mg/kg), and empagliflozin + diazepam. Penicillin (500 IU) was administered intracortically to induce focal epileptiform activity. Electrocorticography (ECoG) recordings were obtained for 180 minutes to assess seizure latency, spike-wave frequency (SWF), and amplitude. Serum and cortical tissue levels of TNF-α, IL-6, and HMGB-1 were quantified using enzyme-linked immunosorbent assay (ELISA).

Results: All treatment groups exhibited a statistically significant increase in latency to the first epileptiform activity compared to the control group. The empagliflozin group showed a marked reduction in SWF between 30 and 180 minutes, particularly during the 121-180-minute period. Tissue TNF-α levels were significantly lower in the empagliflozin + diazepam group compared to the control. Tissue IL-6 levels were lowest in the empagliflozin-only group, whereas serum IL-6 levels were significantly reduced in the combined treatment group. No significant differences in HMGB-1 levels were observed across groups.

Discussion: Empagliflozin demonstrated anticonvulsant and anti-inflammatory effects by delaying seizure onset, reducing SWF, and modulating pro-inflammatory cytokine levels.

Conclusion: Empagliflozin demonstrated anticonvulsant and anti-inflammatory effects by delaying seizure onset, reducing SWF, and modulating pro-inflammatory cytokine levels. These findings suggest that empagliflozin may have therapeutic potential in epilepsy through SGLT-2 inhibition.

Alzheimer's disease (AD) is the most prevalent cause of dementia, accounting for 60-80% of all cases and characterized by amyloid beta (Aβ) plaques and tau protein hyperphosphorylation. Among the signaling mechanisms implicated in AD, protein kinase C (PKC) isoforms and neuron-specific embryonic lethal abnormal vision-4 (ELAV4) have gained increasing attention due to their roles in synaptic plasticity, neuroinflammation, and mRNA stability. This review discusses the potential for targeting the PKC-ELAV4 axis to manage dementia. PKC isoforms, including PKC α, δ, and ε, are involved in amyloid-beta (Aβ) processing, tau phosphorylation, and regulation of mitochondrial activities, whereas ELAV4 stabilizes mRNAs that participate in both the degradation of Aβ (e.g., neprilysin) and the synthesis of Aβ (e.g., beta-site amyloid precursor protein cleaving enzyme 1, BACE1). We reviewed 75 papers published over the last 15 years using search terms such as neuroinflammation, synaptic plasticity, mRNA stability in dementia, ELAV, ELAV4, PKC, and PKC isoforms in databases including PubMed, WOS, and Google Scholar. Results were summarized, compared, and research gaps were identified during data collection and interpretation. ELAV4 can influence the processing of amyloid precursor protein (APP), the precursor of the amyloid-beta peptide, a hallmark of AD. Decreased expression of ELAV4 in the hippocampus is associated with dementia. PKC-δ activates c-Jun N-terminal kinase (JNK) expression, releases Beclin-1 from the Bcl2/Beclin-1 complex, and promotes autophagy. Oxidative stress and PKC η regulate the mitogenactivated protein kinase (MAPK) pathway, leading to tau phosphorylation and neuronal death. PKCε activators and ELAV4 inhibitors have positive effects on cognitive function and dementia management by inhibiting neuroinflammation and neuronal apoptosis, while PKC α, β, δ inhibitors may aid in managing different forms of dementia. This review highlights research gaps and proposes future directions for targeting the PKC-ELAV4 axis as a novel strategy in dementia management.